1,5-benzodiazepine derivatives having CCK and/or gastrin antagonistic activity

ABSTRACT

The present invention relates to compounds of general formula (I) ##STR1## and physiologically acceptable salts thereof wherein the group NR 1  R 2  represents a 5-7 membered saturated heterocyclic ring which may be substituted by one or two methyl groups; R 3  is C 1-6  alkyl, C 3-6  cycloalkyl or phenyl optionally substituted by 1 or 2 halogen atoms; R 4  is phenyl or phenyl substituted by one or two groups selected from the group consisting of halogen, C 1-4  alkyl, trifluoromethyl, trifluoromethoxy or (CH 2 ) n  R 5  wherein n is zero or 1 and R 5  represents C 1-4  alkoxy, hydroxy, nitro, cyano, CO 2  R 6 , S(O) p  CH 3 , NR 7  R 8 , CONR 7  R 8 , SO 2  NR 7  CO(C 1-4 )alkyl, tetrazolyl, carboxamidotetrazolyl, or a 3-trifluoromethyl 1,2,4-triazolyl; R 6  is hydrogen, C 1-4  alkyl or benzyl; R 7  is hydrogen or C 1-4  alkyl, R 8  is hydrogen, C 1-4  alkyl, SO 2  CH 3  or SO 2  CF 3 , X represent hydrogen, C 1-4  alkyl or halogen; m is zero, 1 or 2, and p is zero, 1 or 2. The invention also relates to processes for preparation of these compounds and to their use in medicine as antagonists of gastrin and CCK.

This is a national stage application under 35USC371 of applicationPCT/EP94/01130, filed Apr. 13, 1994.

This invention relates to novel 1,5-benzodiazepine derivatives, toprocesses for their preparation, to pharmaceutical compositionscontaining them and to their use in medicine.

Cholecystokinins (CCK) and gastrin are structurally related peptideswhich exist in gastrointestinal tissue and in the central nervoussystem. Cholecystokinins include CCK-33, a neuropeptide of thirty-threeamino acids in its originally isolated form, its carboxy terminaloctapeptide, CCK-8 (also a naturally-occurring neuropeptide), and 39-and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acidforms, with the miniumum active sequence being the C-terminaltetrapeptide, Trp-Met-Asp-Phe-NH₂ (CCK-4), which is the common structualelement shared by both CCK and gastrin.

CCK and gastrin are gastrointestinal hormones and neurotransmitters inthe neural and peripheral systems and perform their respectivebiological roles by binding to particular receptors located at varioussites throughout the body.

There are at least two subtypes of cholecystokinin receptors termedCCK-A and CCK-B and both are found in the periphery and in the centralnervous system. CCK and gastrin receptor antagonists have been disclosedfor preventing and treating CCK-related and/or gastrin related disordersof the gastrointestinal and central nervous systems of animals, and moreparticularly humans.

U.S. Pat. No. 4,988,692 describes a group of 3-acylamino1-alkyl-5-phenyl 1,5-benzodiazepine derivatives as cholecystokininantagonists. Further the specification teaches that the compounds have asignificantly greater affinity for the CCK-A receptor over the CCK-Breceptor.

We have now found a novel group of 3-ureido 1,5-benzodiazepine compoundswhich are potent and specific antagonists of gastrin and/or CCK and inparticular antagonists of gastrin and/or CCK at the CCK-B receptor.

The present invention thus provides compounds of the general formula (I)##STR2## and physiologically acceptable salts thereof wherein the groupNR₁ R₂ represents a 5-7 membered saturated heterocylic ring which may besubstituted by one or two methyl groups;

R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or phenyl optionally substituted by 1or 2 halogen atoms;

R₄ is phenyl or phenyl substituted by one or two groups selected fromhalogen, C₁₋₄ alkyl, trifluoromethyl, trifluoromethoxy or (CH₂)_(n) R₅wherein n is zero or 1 and R₅ represents C₁₋₄ alkoxy, hydroxy, nitro,cyano, CO₂ R₆, S(O)_(p) CH₃, NR₇ R₈, CONR₇ R₈, SO₂ NR₇ CO(C₁₋₄ alkyl),tetrazolyl, carboxamidotetrazolyl, or a 3-trifluoromethyl1,2,4-triazolyl;

R₆ is hydrogen, C₁₋₄ alkyl or benzyl;

R₇ is hydrogen or C₁₋₄ alkyl,

R₈ is hydrogen, C₁₋₄ alkyl, SO₂ CH₃ or SO₂ CF₃

X represents hydrogen, C₁₋₄ alkyl or halogen;

m is zero, 1 or 2, and p is zero, 1 or 2.

The compounds of the invention possess at least one asymmetric carbonatom and the compounds of the invention include both enantiomers andmixtures thereof including the racemate.

The term alkyl as used herein refers to both straight chain and branchedchain alkyl groups. For example C₁₋₆ alkyl includes methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or hexyl.

The term halogen includes fluorine, chlorine, bromine or iodine.

When R₅ represents a tetrazolyl, carboxamidotetrazolyl or3-trifluoromethyl 1,2,4-triazolyl group these are linked to the rest ofthe molecule via a carbon atom therein and the invention includes alltautomers thereof and the C₁₋₄ alkyl --N substituted derivativesthereof. Examples of such groups include (1H) tetrazol-5-yl,carboxamido-1H-tetrazol-5-yl, 2-methyltetrazol-5-yl and(3-trifluoromethyl-1,2,4-triazol-5-yl.

The group NR₁ R₂ is linked to the rest of the molecule via the nitrogenthereof examples of such groups include pyrrolidino, piperidino,hexamethylenimino-, 2,5-dimethylpyrrolidino, 3,3-dimethylpiperidino,2,6-dimethylpiperidino or 4,4-dimethylpiperidino.

When R₃ represents phenyl optionally substituted by halogen examples ofsuch groups include phenyl optionally substituted by fluorine e.g.phenyl or 2-fluorophenyl, or 4-fluorophenyl.

When R₃ represents C₃₋₆ cycloalkyl examples of such groups includecyclopropyl, cyclopentyl or cyclohexyl.

When R₃ represents C₁₋₆ alkyl examples of such groups include methyl,ethyl, propyl, butyl, 3-methylbutyl or 3,3-dimethylbutyl.

Examples of suitable groups R₄ include phenyl optionally substituted byhalogen e.g. fluorine, alkyl e.g. methyl, alkoxy e.g. methoxy, nitro,cyano, thiomethyl, carboxamido, carboxyl, dimethylamino, cyanomethyl,1H-tetrazol-5-yl, carboxymethyl, or N-methanesulphonylcarboxamido.

A preferred class of compound according to the invention are thosewherein the group NR₁ R₂ represent pyrrolidino, piperidino,3,3-dimethylpiperidino 4,4-dimethylpiperidino, 2,6-dimethylpiperidino or2,5-dimethylpyrrolidino. Within this class the group NR₁ R₂ isconveniently pyrrolidino, piperidino, or 3,3-dimethylpiperidino.

The group X is conveniently halogen e.g. bromine, fluorine or fluorineor more particularly hydrogen.

A further preferred class of compounds of formula (I) are those whereinR₃ is phenyl, 2-fluorophenyl or cyclohexyl and more particularly2-fluorophenyl or cyclohexyl.

Another preferred class of compounds of formula (I) are those wherein R₄is phenyl or phenyl substituted by methyl e.g. 3-methylphenyl or3,5-dimethylphenyl, 3-dimethylaminophenyl, phenyl substituted byfluorine e.g. 4-fluorophenyl, phenyl substituted by methoxy e.g.3-methoxyphenyl or 4-methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl,3-carboxamidophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl, or3-(1H)-tetrazol-5-yl-phenyl.

A particularly preferred group of compounds according to the inventionare those wherein NR₁ R₂ represents pyrrolidino, piperidine or3,3-dimethyl-, piperidino, R₃ represents 2-fluorophenyl or cyclohexyl,and X represents a hydrogen atom. Within this group particularlypreferred compounds include those wherein R₄ is phenyl, 4-fluorophenyl,3-dimethylaminophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or3-(1H)-tetrazolyl-5-yl-phenyl.

A particularly preferred compound of the inventionis:-1-[1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-3-(4-fluoro-phenyl)ureaand enantiomers thereof.

Further preferred compounds of the invention include3-{3-[1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid;(3-{3-[1-(2-Fluoro-phenyl)-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-phenyl)-aceticacid;3-{3-[1-[2-(3,3-Dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-(2-fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid and enantiomers thereof.

The physiologically acceptable salts of the compounds of formula (I)include conventional salts formed for example from pharmaceuticallyacceptable inorganic or organic acids as well as quaternary ammoniumacid addition salts. Examples of suitable salts include hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic,propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric,pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, fumaric, toluenesulphonic, methanesulphonic,naphthalene-2-sulphonic, benzenesulphonic and the like. Other acids suchas oxalic, while not in themselves pharmaceutically acceptable, may beuseful in the preparation of salts useful as intermediates in obtainingthe compounds of the invention and their pharmaceutically acceptablesalts.

References hereinafter to a compound according to the invention includesboth compounds of formula (I) and their pharmaceutically acceptablesalts and solvates.

Compounds of the invention modulate the effect of gastrin and/or CCK inmammals. In particular compounds of the invention are antagonists ofgastrin and/or CCK.

Compounds of the invention have been shown to be antagonists of CCK,particularly at CCK-B receptors as demonstrated for example by thecompound's ability to inhibit the contractile actions of CCK-4 in thepresence of a CCK-A antagonist, in the guinea-pig isolated ileumlongitudinal muscle-myenteric plexus.

The preparation and use of guinea-pig isolated ileum longitudinalmuscle-myenteric plexus has been described by K-H Buchheit et al inNauynSchmeideberg's Arch. Pharmacol., (1985), 329, p36-41 and by V. L.Lucaites et al in J. Pharmacol. Exp. Ther., (1991) 256,695-703.

Compounds of the invention have also been shown to have a greateraffinity for the CCK-B receptor than for the CCK-A receptor. This may bedetermined using the CCK receptor binding assays described by Fornos etal J. Pharmacol Exp. Ther., 261 1056-1063, 1992.

Alternatively the binding affinity of compounds of the invention forCCK-A and CCK-B receptors may be determined using HeLa cell membranesthat are transfected with the human CCK-B receptor or, COS-M6 cellmembranes that are transiently transfected with the human CCK-Areceptor.

Compounds of the invention have also been shown to be antagonists ofgastrin as demonstrated by their ability to inhibitpentagastrin-stimulated acid secretion from rat isolated gastric mucosausing the procedure described by J. J. Reeves and R. Stables in Br. J.Pharmac,. 1985 86, p.677-684.

Compounds of the invention have also been shown to inhibit pentagastrinstimulated acid secretion in conscious gastric fistula rats using themethods described by Hedges and Parsons Journal of Physiology 1977, 267,181-194.

The compounds of the invention are therefore useful for the treatmentand/or prevention of disorders in mammals, especially humans, wheremodification of the effects of gastrin or CCK is of therapeutic benefit.Thus the compounds of the invention are useful for the treatment ofgastrointestinal disorders especially those where there is an advantagein lowering gastric acidity. Such disorders include peptic ulceration,reflux oesophagitis and Zollinger Ellison syndrome. They may also beuseful for the treatment of gastrointestinal disorders such as irritablebowel syndrome, excess pancreatic secretion, acute pancreatitis,motility disorders, antral G cell hyperplasia, fundic mucosalhyperplasia or gastrointestinal neoplasms. The compounds of theinvention are also useful for the treatment of central nervous systemdisorders where CCK and/or gastrin are involved. For example anxietydisorders (including panic disorder, agoraphobia, social phobia, simplephobia, obsessive compulsive disorders, post traumatic stress disorder,and general anxiety disorder), depression, tardive dyskinesia,Parkinson's disease or psychosis. They may also be useful for thetreatment of dependency on drugs or substances of abuse and withdrawal,Gilles de la Tourette syndrome, or dysfunction of appetite regulatorysystems; as well as the treatment of certain tumours of the loweroesophagus, stomach, intestines and colon. Compounds of the inventionare also useful for directly inducing analgesia, or enhancing opiate ornon-opiate mediated analgesia, as well as anaesthesia or loss of thesensation of pain.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

According to another aspect the invention provides the use of a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereoffor the manufacture of a medicament for the treatment of conditionswhere modification of the effects of gastrin and/or CCK is oftherapeutic benefit.

According to a further aspect of the invention we provide a method forthe treatment of a mammal, including man, in particular in the treatmentof conditions where modification of the effects of gastrin and/or CCK isof therapeutic benefit which method comprises administering an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof to the patient.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms.

It will further be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. In general however doses employed for adult humantreatment will typically be in the range of 1-2000 mg per day e.g 10-500mg per day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

Compounds of the invention which antagonise the function of CCK inanimals, may also be used as feed additives to increase the food intakein animals in daily dosages of around 1 mg/kg to 10 mg/kg.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with one or more pharmaceutically acceptablecarriers therefor and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) must be `acceptable` in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The compositions of the invention include those in a form especiallyformulated for oral, buccal, parenteral, implant, or rectaladministration. Oral administration is preferred.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example, syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone;fillers, for example, lactose, sugar, microcrystalline cellulose,maize-starch, calcium phosphate or sorbitol; lubricants, for example,magnesium stearate, stearic acid, talc, polyethylene glycol or silica;disintegrants, for example, potato starch or sodium starch glycollate,or wetting agents such as sodium lauryl sulphate. The tablets may becoated according to methods well known in the art. Oral liquidpreparations may be in the form of, for example, aqueous or oilysuspensions, solutions emulsions, syrups or elixirs, or may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; and preservatives, for example, methyl orpropyl p-hydroxybenzoates or ascorbic acid. The compositions may also beformulated as suppositories, e.g. containing conventional suppositorybases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The composition according to the invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

The composition according to the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The compositions according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

Compounds of general formula (I) and salts thereof may be prepared bythe general methods outlined hereinafter. In the following description,the groups R₁ -R₈ and X are as defined for the compounds of formula (I)unless otherwise stated.

According to a first general process A, compounds of formula (I) may beprepared by the reaction of an amine of formula (II) wherein R₁, R₂, R₃,X and m have the meanings defined in formula (I). ##STR3## with acompound R₄ Y, wherein R₄ Y is an isocyanate of formula (III), carbamoylchloride of formula (IV), imidazolide of formula (V), or an optionallysubstituted phenyl carbamate of formula (VI) wherein R_(a) is anoptionally phenxoy group. ##STR4##

The reaction conveniently takes place in the presence of a suitablesolvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g.tetrahydrofuran) or nitrile (e.g. acetronitrile) or a mixture thereof ata temperature in the range of 0°-80° C.

Isocyanates of formula (III) may be purchased or prepared by thereaction of amines H₂ N--R₄ with phosgene or triphosgene in a suitablesolvent such as methylene chloride. Carbamoyl chlorides of formula (IV)are also prepared by the reaction of amines H₂ NR₄ with phosgene ortriphosgene in a suitable solvent such as methylene chloride.Imidazolides of formula (VI) are prepared by treatment of amines H₂N--R₄ with carbonyl diimidazole in a suitable solvent (dichioromethane,ether, tetrahydrofuran) at a temperature ranging from 0°-80° C.(conveniently at room temperature). Optionally substituted phenylcarbamates of formula (VI) are prepared by the reaction of amines H₂N--R₄ with the appropriate chloroformate R_(a) COCl in the presence of abase (pyridine, triethylamine) in a suitable solvent (dichloromethane)and at a temperature of 0°-50° C.

According to a further general process B, compounds of formula (I) maybe prepared by reaction of an intermediate of formula (VII). ##STR5##wherein Y is the group --NCO, --NHCOCl or NHCOR_(a) wherein IR_(a) is anoptionally substituted phenoxy group or a 1-imidazole group with anamine (VIII)

    H.sub.2 N--R.sub.4                                         (VIII)

and optionally in the the presence of a base such as a tertiary amine(e.g. triethylamine).

The reaction conveniently takes place in a suitable solvent such as ahalogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g.tetrahydrofuran) or an amide (e.g. N,N-dimethyl formamide) optionally ata temperature ranging from room temperature to the reflux temperature ofthe solvent.

Conveniently the compound of formula (VII) are prepared in situ from theamine (II).

In a particular aspect of the process (B) when Y is the group NHCOR_(a)and R_(a) is a 1-imidazole group, the imidazolide (VII) may be formed insitu in which case the amine of formula (VIII) will be mixed with thecompound of formula (II) ##STR6## in the presence of carbonyldiimidazoleunder the aforementioned conditions.

For process B when Y is the group NHCOR_(a) and R_(a) is optionallysubstituted phenoxy group the reaction with the primary amine (VIII) ispreferably carried out in the presence of a base such as a tertiaryamine e.g. triethylamine.

For process B when Y is the isocyanate group --N═C═O the reaction withthe primary amine (VIII) is preferably carried out in an aprotic solventsuch as a halohydrocarbon e.g. methylene chloride. Conveniently theisocyanate is generated in situ prior to the addition of the primaryamine (VIII).

The compounds of formula (VII) wherein R_(a) is an optionallysubstituted phenoxy group may be prepared from the primary amine (II) byreaction with the corresponding optionally substituted phenylchloroformate in the presence of a base such as pyridine. The reactionmay be carried out in a solvent such as a halohydrocabon e.g.dichloromethane and at a temperature from 0°-500°.

Compounds of formula (VII) wherein R_(a) is a 1-imidazole group may beprepared by reacting a compound of formula (II) with carbonyldiimidazolein the presence of a suitable solvent such as a halogenated hydrocarbon(e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) at atemperature ranging from 0° to 80° (conveniently at room temperature).

Compounds of formula (VII) wherein Y is the isocyanate grouping --N═C═Oor carbamoyl chloride --NHCOCl may be prepared from the primary amine(II) by reaction with phosgene (COCl₂) or triphosgene in a suitablesolvent such as methylene chloride.

According to a further general process C compounds of formula (I) mayalso be prepared by a reaction of the compound of formula (IX) ##STR7##with the halide R₂ R₁ NCOCH₂ Z wherein Z=a leaving group e.g. bromine,chlorine or iodine.

The reaction is conveniently carried out by treating the compound offormula (IX) with a strong base such as sodium hydride in a polaraprotic solvent such as N,N-dimethylformamide followed by reaction withthe alkylating agent R₁ R₂ NCOCH₂ Z.

Compounds of formula (II) may be prepared by reduction of compounds offormula (X) ##STR8## wherein W is CH--N₃ or C═N--NHPh.

Compounds of formula (X) wherein W is CH--N₃ may be reduced to acompound of formula (II) by hydrogenation in the presence of a suitablecatalyst such as palladium, on a support such as carbon or calciumcarbonate, or platinum (IV) oxide. The reaction conveniently takes placein the presence of a solvent such as an alkanol (e.g. ethanol) an ester(e.g. ethyl acetate) or acetic acid.

Compounds of formula (X) wherein W is C═N--NHPh may be reduced to acompound of formula (II) by reaction with zinc and acetic acid. Thisreaction may be carried out a temperature with the range 0°-500.

Compounds of formula (X) wherein W is CHN₃ may be prepared from acompound of formula (X) wherein W is CH₂ by treatment with a strong basesuch as sodium hydride or potassium tert-butoxide followed bytri-isopropyl benzenesulphonyl azide. The reaction conveniently takesplace in a solvent such as an ether (e.g. tetrahydrofuran) at atemperature in the range of -78° to 20°.

Compounds of formula (X) in which W is C═NNHPh may be prepared byreaction of the ortho-phenylenediamine (XI) with the diacid chloride(XII), in a suitable solvent such as an ether e.g. tetrahydrofuran##STR9##

Compounds of formula (X) wherein W is CH₂ may be prepared by reaction ofthe compound of formula (XI) with the diacid chloride (XIII) ##STR10##

Compounds of formula (XI) are either known compounds or may be preparedby analogous methods. Thus for example a compound of formula (XI) may beprepared by alkylation of the amine (XIV). ##STR11##

Thus the amine (XIV) may be reacted with the compound R₁ R₂ NCOCH₂ Z, inwhich Z is chlorine or bromine, optionally in the presence of sodiumiodide in a solvent such as N,N-dimethylformamide.

In general, the compounds of formula (III), (IV), (V) and (VI) areeither known compounds or may be prepared according to methods simlar tothose used for the preparation of known compounds.

According to a further process (D) a compound of formula (I) may beprepared from the compound of formula (XV) wherein R_(b) is hydrogen##STR12## by reaction of an activated derivative thereof with the amineR₁ R₂ NH. Conveniently the reaction is carried out using the acid in thepresence of a diimide such as dicyclohexyl carbodimide andhydroxybenzotriazole in a solvent such as dichloromethane or in thepresence 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline in a solventsuch as dimethoxyethane.

The compounds of formula (XV) wherein R_(b) is a hydrogen may beprepared by hydrolysis of the corresponding compound of formula (XV)wherein R_(b) is a t-butyl group, for example by reaction withtrifluoroacetic acid. The compound of formula (XV) wherein R_(b) ist-butyl may be prepared by alkylation of the corresponding compound offormula (IX) with the halo ester Z--CH₂ CO₂ R_(b) wherein Z is halogen.Alternatively the compound (XV) wherein R_(b) is t-butyl may be preparedusing the general processes A and B described above for preparing thecompounds of formula (I) but starting with the appropriate N-substitutedbenzodiazepine derivative.

According to a further process (E) a compound of formula (I) may beconverted into another compound of formula (I) using conventionaltechniques.

Thus compounds of formula (I) wherein R₄ is a phenyl group substitutedby a carboxyl or carboxymethyl group may be prepared by hydrolysis ofthe corresponding compound of formula (I) wherein R₄ is a phenyl groupsubstituted by an alkoxycarbonyl or alkoxycarbonylmethyl group.

Compounds of formula (IX) may be prepared from the diamine (XIV), inwhich the primary amino group is protected as an p-methoxybenzylderivative thereof, using the general procedures described above forpreparing the compounds of formula (I) from the correspondingorthophenylenediamine (XI) followed by removal of the N-protecting groupp-methoxybenzyl using conventional procedures.

Compounds of formula (I) contain at least one asymmetric carbon atom,namely the carbon atom of the diazepine ring to which the substitutedurea grouping is attached. Specific enantiomers of the compounds offormula (I) may be obtained by resolution of the racemic compound usingconventional procedures such as chiral HPLC. Alternatively the requiredenantiomer may be prepared from the corresponding enantiomer amine offormula (II) using any of the processes described above for preparingcompounds of formula (I) from the amine (II). The enantiomers of theamine (II) may be prepared from the racemic amine (II) usingconventional procedures such as salt formation with a suitably opticallyactive acid such as R-camphorsulphonic acid or by preparative chiralHPLC.

In order that the invention may be more fully understood the followingexamples are given by way of illustration only.

In the Intermediates and Examples unless otherwise stated. Meltingpoints (mp) are determined on a Gallenkamp mp apparatus and areuncorrected. All temperatures refers to °C. Column chromatography wascarried out over silica gel. T.I.c. refers to thin layer chromatographyon silica plates. Dried refers to solutions dried over anhydrous sodiumsulphate. The following abbreviation are also used in the Examples.EA=ethyl acetate, DMF=N,N-dimethylformamide, THF=tetrahydrofuran,DE=diethyl ether, DCM=dichloromethane, MeOH=methanol, AcOH=acetic acid,ee=enantiomeric excess, R_(T) =retention time.

Intermediate 1

Cyclohexyl-(2-nitro-phenyl)-amine

A mixture of 2-chloronitrobenzene (20 g), potassium carbonate (35 g) andcopper (I) iodide (1.21 g)in cyclohexylamine (43.6 ml) was heated at150° under nitrogen for 18 h. The mixture was allowed to cool to roomtemperature and was adsorbed onto silica. This was chromatographed withhexane-EA (98:2) as eluent to give the title compound (22.94 g) as anorange solid.

T.I.c. (98:2 hexane-EA) Rf 0.38

Intermediate 2

N-Cyclohexyl-benzene-1,2-diamine

A solution of Intermediate 1 (10 g) in ethyl acetate (400 ml) washydrogenated at 23° and 1 atm. pressure over 10 % palladium on carbon (1g) for 4 h. The catalyst was removed by filtration through hyflo and thefiltrate evaporated to give the title compound (8.5 g) as an orange oil.

T.I.c. (9:1 hexane-EA) Rf 0.36

Intermediate 3

2-(2-Cyclohexylamino-phenylamino)-1-pyrrolidin-1-yl-ethanone

A mixture of Intermediate 2 (8.5 g),2-oxo-2-(pyrrolidin-1-yl)ethylbromide (9.4 g) and potassium carbonate(18.5 g) in dry DMF (250 ml) was stirred at 23° under nitrogen for 18 h.The mixture was poured into water (600 ml) and extracted with ethylacetate (3×300 ml). The combined extracts were washed with water (3×300ml) and saturated brine (200 ml), dried and evaporated to give a brownoil. This was chromatographed with hexane-EA (1:1) as eluent to give thetitle (9.8 g) as a cream solid, m.p.108°-110°.

T.l.c. (1:1 hexane-EA) Rf 0.42

Intermediate 4

1-Cyclohexyl-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-3-(phenyl-hydrazono)-1.5-dihydrobenzo[b][1.4]diazepine-2,4-dione

Solutions of Intermediate 3 (9.8 g) and2-(phenyl-hydrazono)-propanedioyl dichloride (8.36 g) in dry THF (75 ml)were added at equal rates to dry THF (75 ml) cooled to -10° undernitrogen. When the addition was complete the mixture was allowed to warmto room temperature and stir for 3 h. The solvent was removed byevaporation to give the crude title-compound (19.5 g) as a yellowcrunchy foam.

T.I.c. (DE) Rf 0.23

Intermediate 5

3-Amino-1-cyclohexyl-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1.5-dihydrobenzo[b][1,4]diazepine-2,4-dione

A solution of Intermediate 4 (19 g) in glacial acetic acid (200 ml) wasadded dropwise to a stirring suspension of zinc dust (15 g) in glacialacetic acid. The mixture was stirred at 230 for 1.5 h whereupon the zincwas removed by filtration through hyflo and the filtrate evaporated togive a red oil. This was partitioned between water (200 ml) and ethylacetate (75 ml). The aqueous portion was adjusted to pH9 with solid Na₂CO₃ and extracted with ethyl acetate (4×100 ml). The combined organicextracts were dried and evaporated to give a brown oil which waschromatographed with DCM-MeOH (95:5) as eluent to give the title (7.4 g)as a pink crunchy foam.

T.I.c. (95:5 DCM-MeOH) Rf 0.26

Intermediate 6

3-{3-[-1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid,benzyl ester

Triethylamine (108 μl) and triphosgene (77 mg) were added sequentiallyto a solution of 3-amino-benzoic acid benzyl ester (177 mg) in dry THF(1 0 ml) at 0° under nitrogen. More triethylamine (108 μl) was added andstirring continued at 0° for 30 min. A solution of Intermediate 5 (250mg) in dry THF (10 ml) was added and stirring continued at 23° for 18 h.The mixture was then partitioned between 2N hydrochloric acid (50 ml)and ethyl acetate (50 ml). The dried organic extract was evaporated andthe residue chromatographed with EA-hexane (2:1) as eluent to give thetitle compound (320 mg) as a pale yellow solid.

T.I.c. (2:1 EA-hexane) Rf 0.17

I.r. (Solution in CHCl₃)3384;2939;1690;1658;1423 cm¹

Intermediate 7

3-Nitro-benzoic acid tert-butyl ester

A solution of 3-nitrobenzoic acid (1.4 g) in dry toluene (10 ml) wastreated with N,N-dimethylformamide di-tertbutyl acetal (10 ml). Themixture was heated under reflux for 18 h then cooled, diluted with ethylacetate and washed consecutively with water, 8% sodium bicarbonatesolution and saturated brine. The dried organic phase was evaporated togive the title compound (1.02 g) as a yellow oil.

T.I.c. (97:3 DCM-MeOH) Rf 0.66

Intermediate 8

3-Amino-benzoic acid tert-butyl ester

A solution of Intermediate 7 (1 g) in ethanol (20 ml) was hydrogenatedat 23° and 1 atm pressure in the presence of 10% palladium on carbon ascatalyst (200 mg). After 2 h the mixture was filtered through hyflo andthe filtrate evaporated. The residue was chromatographed with DCM-MeOH(97:3) as eluent to give the title compound (727 mg) as a colourlessoil.

T.I.c. (97:3 DCM-MeOH) Rf 0.35

lntermediate 9

(3- Nitro-phenyl)-acetic acid benzyl ester,

A mixture of 3-nitrophenylacetic acid (5 g), benzyl alcohol (2.9 ml) and4,4-dimethylaminopyridine (300 mg) in dry dichloromethane (50 ml) wastreated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (7.4 g). Theresulting yellow mixture was stirred at 23° for 3 days whereupon thesolvent was removed in vacuo. The residue was partitioned between water(100 ml) and ethyl actate (100 ml) and the organic phase washed withwater (2×100 ml) and saturated brine (100 ml) then dried and evaporated.The residue was chromatographed with hexane-EA (4:1) as eluent thenagain with isohexane-DCM (1:1) as eluent to give the title compound(2.05 g) as a pale yellow oil.

T.I.c. (4:1 hexane-EA) Rf 0.35

Intermediate 10

(3-Amino-phenyl)-acetic acid benzyl ester

A solution of Intermediate 9 (2.05 g) in ethyl acetate (100 ml) washydrogenated at 23° and 1 atm pressure in the presence of 5% platinum oncarbon (200 mg) as catalyst. After 90 min the mixture was filteredthrough hyflo and the filtrate evaporated to give the title compound(1.77 g) as a pale yellow oil T.I.c. (DCM) Rf 0.35

Intermediate 11

(2-Fluoro-phenyl)-(2-nitro-phenyl)-amine

A mixture of 2-fluoroaniline (5.0 g), potassium carbonate (2.5 g) andcopper(I)iodide (414 mg) in 2-fluoronitrobenzene (16.9 ml) was heated to180° under nitrogen for 18 h. The cooled mixture was poured into water(300 ml) and extracted with ethyl acetate (2×250 ml) then the combinedextracts were washed with saturated brine and evaporated. The residualbrown oil was azeotroped with ethanol/water then toluene. The residuewas chromatographed with hexane-DE (100:0 to 95:5) to give the titlecompound (3.25 g) as a bright orange solid, m.p.58°-9°.

T.I.c.(95:5 hexane-DE) Rf 0.45

Intermediate 12

N-(2-Fluoro-phenyl)-benzene-1,2-diamine

A solution of Intermediate 11(15.6 g)in ethyl acetate (400 ml) washydrogenated at 23° and 1 atm pressure in the presence of 5% platinum oncarbon (2 g) as catalyst. After 1 h the mixture was filtered throughhyflo and the filtrate evaporated to give the title compound (13.45 g)as a yellow solid.

T.I.c. (9:1 hexane-DE) Rf 0.25

Intermediate 13

2-[2-(2-Fluoro-phenylamino)-phenylamino]-1-pyrrolidin-1-yl-ethanone

A solution of 2-oxo-2-(pyrrolidin-1-yl)ethylbromide (12.8 g) in dry DMF(60 ml) was added dropwise to a mixture of Intermediate 12 (13.45 g) andpotassium carbonate (27.5 g) in dry DMF (100 ml) at 23° under nitrogen.The mixture was stirred at 60° for 4 h then poured into 2N sodiumcarbonate solution (500 ml) and extracted with ethyl acetate (400 ml).The organic extract was washed with water (2×250 ml) and .saturatedbrine (250 ml), dried and evaporated. The residue was chromatographedwith hexane-DE (50:50 to 0:100) as eluent to give the title compound(14.12 g) as a pale brown solid.

T.I.c. (DE) Rf 0.53

Intermediate 14

1-(2-Fluoro-phenyl)-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-3-(phenyl-hydrazono)-1.5-dihydro-benzo[b][1.4]diazepine-2,4-dione

Solutions of Intermediate 13 (14.12 g) and2-(phenyl-hydrazono)-propanedioyl dichloride (11.04 g) in dry THF (100ml) were added simultaneously and dropwise at equal rates to dry THF(100 ml) cooled to -10° under nitrogen. When the addition was completethe mixture was allowed to warm to room temperature and stir for 3.5 h.The solvent was removed by evaporation to give the crude title compound(23 g) as a yellow crunchy foam.

T.I.c. (EA) Rf 0.5

Intermediate 15

3-Amino-1-(2-fluoro-phenyl)-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1,5-dihydrobenzo[b][1.4]diazepine-2,4-dione

A solution of Intermediate 14 (23 g) in glacial acetic acid (200 ml) wasadded dropwise to a stirred suspension of zinc dust (22.2 g) in glacialacetic acid (100 ml) in a cold water-bath. The mixture was stirred at23° for 2.5 h whereupon the zinc was removed by filtration through hyfloand the filtrate evaporated. The residue was partitioned between water(150 ml) and ethyl acetate (100 ml) and the aqueous portion basifiedwith solid Na₂ CO₃. The layers were separated and the aqueous phasefurther extracted with ethyl acetate then the combined organic extractswere washed with saturated brine, dried and evaporated. The residue waschromatographed with EA-MeOH (100:0 to 95:5) as initial eluent followedby DCM-MeOH (80:20) to give the title compound (11.07 g) as a fawnpowder.

T.I.c. (95:5 DCM MeOH) Rf 0.23

Intermediate 16

(3-{3-[1-(2-Fluoro-phenyl)-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-phenyl)-aceticacid benzyl ester

A solution of Intermediate 15 (3 g) in dry dichloromethane (40 ml) wasadded dropwise to a stirred solution of phosgene in toluene (60 ml)under nitrogen. The resulting mixture was stirred at 23° for 4 h thennitrogen was bubbled through the mixture into ammonia solution for 18 h.The mixture was then evaporated and the residue dried at 60° in vacuofor 3 h to give the intermediate isocyanate (3.3 g) as a buff solidwhich was used without further characterisation. A solution of thisisocyanate (400 mg)in dry dichloromethane (3 ml) was added dropwise to astirred solution of (3-amino-phenyl)-acetic acid benzyl ester (241 mg)in dry dichloromethane (2 ml) at 23° under nitrogen. After 60 min thesolvent was removed in vacuo and the residue triturated with diethylether. The solid was filtered off and dried to give the title compound(263 mg) as an off-white solid, m.p.104°-6°.

T.I.c. (EA) Rf 0.54

Intermediate 17

2-Bromo-1-(3,3-dimethyl-piperidin-1-yl)-ethanone

A mixture of 3,3-dimethylpiperidine (10 g) and triethylamine (12.3 ml)in dry dichloromethane (50 ml) was added dropwise to an ice-coldsolution of bromoacetyl bromide (7.7 ml) in dry dichloromethane (100ml). The mixture was stirred at 23° for 18 h then recooled to 0°. Icedwater (200 ml) was added and the layers separated. The aqueous layer wasfurther extracted with dichloromethane (2×200 ml) then the combinedextracts were washed with 2N HCl (200 ml) and saturated brine (200 ml),dried and evaporated to give the title compound (17.28 g) as a brownoil.

T.I.c. (DE) Rf 0.49

Intermediate 18

1-(3,3-Dimethyl-piperidin-1-yl)-2-[2-(2-fluoro-phenylamino)-phenylamino]-ethanone

A mixture of Intermediate 12 (3 g)) and potassium carbonate (6.15 g) indry DMF (10 ml) was treated with a solution of2-bromo-1-(3,3-dimethyl-piperidin-1-yl)-ethanone (3.5 g) in dry DMF (10ml) and stirred at 23° under nitrogen for 3 days. The mixture was pouredinto water and extracted with ethyl acetate. The combined extracts werewashed with water and saturated brine, dried and evaporated to give abrown oil. This was chromatographed with DCM-MeOH (100:0 to 97:3) aseluent to give the title compound (3.17 g) as a pale brown foam.

T.I.c. (DCM) Rf 0.23

Intermediate 19

1-[2-(3,3-Dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-(2-fluoro-phenyl)-3-(phenylhydrazono)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

Solutions of Intermediate 18 (3.08 g) and2-(phenyl-hydrazono)-propanedioyl dichloride (2.12 g) in dry THF (100ml) were added at equal rates to dry THF (50 ml) cooled to -10° undernitrogen. When the addition was complete the mixture was allowed to warmto room temperature and stirred for 2 h. The solvent was removed byevaporation to give the crude title compound (5.25 g) as a yellowcrunchy foam.

T.I.c. (95:5 DCM-MeOH) Rf 0.68

Intermediate 20

3-Amino-1-[2-(3,3-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-(2-fluoro-phenyl)-1,5-dihydro-benzo[b][1.4]diazepine-2,4-dione

A solution of Intermediate 19 (5.15 g) in glacial acetic acid (75 ml)was added dropwise to a stirring suspension of zinc dust (4.47 g) inglacial acetic acid (50 ml) in a cold water-bath. The mixture wasstirred at 23° for 6 h whereupon the zinc was removed by filtrationthrough hyflo and the filtrate evaporated. The residue was partitionedbetween water and ethyl actate and the aqueous portion basified withsolid Na₂ CO₃. The organic extract was washed with saturated brine,dried and evaporated. The residue was chromatographed with DCM-MeOH(95:5) as eluent to give the title compound (2.38 g) as a pale brownsolid.

T.I.c. (95:5 DCM-MeOH) Rf 0.18

Intermediate 21

3-{3-[1-[2-(3,3-Dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-(2-fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid tert-butyl ester

Triethylamine (0.31 ml) and triphosgene (217 mg) were added sequentiallyto a solution of 3-amino-benzoic acid tert-butyl ester (423 mg) in dryTHF (10 ml) at 0° under nitrogen. More triethylamine (0.31 ml) was addedand stirring continued at 0° for 30 min. A solution of Intermediate 20(800 mg) in dry THF (10 ml) was added and stirring continued at 23° for18 h. The mixture was then partitioned between phosphate buffer solution(pH6.5) and dichloromethane. The combined organic extracts were washedwith saturated brine, dried and evaporated and the residuechromatographed with DCM-MeOH (97:3) as eluent to give a pale greensolid which was triturated with DE-hexane (1:1) to give the titlecompound (1.07 g) as a white solid, m.p. 170°.

T.I.c. (97:3 DCM-MeOH) Rf 0.15

EXAMPLE 1

1-[1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepin-3-yl]-3-(4-fluoro-phenyl)urea

4-Fluorophenyl isocyanate (650 μl) was added to a solution ofIntermediate 5 (2 g) in dry dichloromethane (50 ml) at 23° undernitrogen. The resulting mixture was stirred for 1 h then adsorbed ontosilica and chromatographed with EA-MeOH (100:0 to 95:5) as eluent togive the title compound (1.92 g) as a white solid, m.p. 181°-3°.

T.I.c. (EA) Rf 0.42

The compound of Example 1 (1.7 g) was separated into its 2 enantiomers(Isomer 1 and Isomer 2) by chiral HPLC.

Column: Chiralcel OD 25 cm×20 mm id

Eluent: Hexane-EtOH (70:30)

Flow rate: 20 ml min⁻¹

Detection: uv@254 nm

Isomer 1, (452 mg) as a white solid - R_(T) 8.6 min. H.p.l.c. >99.5% ee

T.I.c. (EA) Rf 0.42

I.r. (Solution in CHCl₃) 3622;3091;2938;2895;2403;1657;1515;1425;1189;1047;929 cm⁻¹

Isomer 2, (488 mg) as a white solid- R_(T) 15.1 min. H.p.l.c. 98.8%ee

T.I.c. (EA) Rf 0.42

I.r. (KBr disc) 3366;2935;1695;1657;1558;1510;1422;1206;833;763 cm⁻¹

EXAMPLE 2

3-{3-[1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepin-3-yl]-ureido}-benzoicacid

A solution of Intermediate 6 (248 mg) in ethyl acetate (10 ml) and THF(5 ml) was hydrogenareal at 23° and 1 atm pressure overnight in thepresence of 10% palladium on carbon (25 mg) as catalyst. More catalyst(25 mg) was added and hydrogenation continued for 2 h whereupon themixture was filtered through hyflo and the filtrate evaporated to givethe title compound (216 mg) as a white solid, m.p.275°-6°.

T.I.c. (100:2 EA-AcOH) Rf 0.25

I.r. (KBr disc) 3369;2935;1700;1659;1557;1499;1431;1233;760 cm⁻¹

(3-{3-[1-(2-Fluoro-phenyl)-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-phenyl)-aceticacid

A solution of Intermediate 16 (177 mg) in THF (10 ml) was hydrogenatedat 23° and 1 atm pressure in the presence of 10% palladium on carbon (10mg) as catalyst. After 90 min the mixture was filtered through hyflo andthe filtrate evaporated to give the title compound (67 mg) as a whitesolid, m.p. 197°-9°.

T.I.c. (EA) Rf 0.17

I.r. (KBr disc) 3331;1708;1651;1562;1499;1454;1403;1238;761 cm⁻¹

EXAMPLE 4

3-{3-[1-[2-(3,3-Dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-(2-fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid

A solution of Intermediate 21 (400 mg) indichloromethane (20 ml) wastreated with trifluoroacetic add (2 ml) and stirred at 23° undernitrogen for 1 h. The mixture was concentrated in vacuo and the residuechromatographed with DCM-MeOH (95:5) as eluent to give the titlecompound (344 mg) as a white solid, m.p.225° dec.

T.I.c. (95:5 DCM-MeOH) Rf 0.26

Using the general processes A, B, C and D described above the followingcompounds of the invention have also been prepared.

                  TABLE 1                                                         ______________________________________                                         ##STR13##                                                                    Ex. No   X       R.sub.5    mp    Process                                     ______________________________________                                        5        H       3,5-diCH.sub.3                                                                           254-5°                                                                       A                                           6        H       4-OCH.sub.3                                                                              180-2°                                                                       A                                           7        H       3-F        188-90°                                                                      A                                           8        H       3-NO.sub.2 173-5°                                                                       A                                           9        H       3-CH.sub.2 CN                                                                            210-2°                                                                       A                                           10       H       H          216-8°                                                                       A                                           11       H       3-CONH.sub.2                                                                             275-7°                                                                       A                                           12       H       3-N(CH.sub.3).sub.2                                                                      251-3°                                                                       A                                           13       Br      4-F        *Rf 0.3                                                                             D                                           ______________________________________                                         *T.I.c. cyclohexane:E A:AcOH 1:1:0.0.4                                   

                  TABLE 2                                                         ______________________________________                                         ##STR14##                                                                    Ex. No R.sub.3  R.sub.5       mp      Process                                 ______________________________________                                        14     Ph       3-tetrazolyl   243°                                                                          A                                       15     Ph       3-CH.sub.3     234-6°                                                                        A                                       16     Ph       3-CONHSO.sub.2 CH.sub.3                                                                      199-200°                                                                      B                                       17     2-F-Ph   4-F            155-7°                                                                        A                                       18     2F-Ph    3-CH.sub.3     195-7°                                                                        A                                       19     2F-Ph    3-CO.sub.2 H  -225-7°                                                                        B                                       ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR15##                                                                    Ex. No.   NR.sub.1 R.sub.2                                                                           mp        Process                                      ______________________________________                                        20                                                                                       ##STR16##   240°                                                                             A                                            21                                                                                       ##STR17##   170°                                                                             A                                            22                                                                                       ##STR18##   260°                                                                             A                                            23                                                                                       ##STR19##   220-5° dec                                                                       C                                            24                                                                                       ##STR20##   255-8°                                                                           D                                            ______________________________________                                    

Pharmacy Examples

Tablets

    ______________________________________                                        a.       Active ingredient    50 mg                                                    Lactose anhydrous USP                                                                              163 mg                                                   Microcrystalline Cellulose NF                                                                      69 mg                                                    Pregelatinised starch Ph.Eur.                                                                      15 mg                                                    Magnesium stearate USP                                                                             3 mg                                                     Compression weight   300 mg                                          ______________________________________                                    

The active ingredient, microcrystalline cellulose, lactose andpregelatinised starch are sieved through a 500 micron sieve and blendedin a suitable mixer. The magnesium stearate is sieved through a 250micron sieve and blended with the active blend. The blend is compressedinto tablets using suitable punches.

    ______________________________________                                        b.       Active ingredient    50 mg                                                    Lactose monohydrate USP                                                                            120 mg                                                   Pregelatinised starch Ph.Eur.                                                                      20 mg                                                    Crospovidone NF      8 mg                                                     Magnesium stearate USP                                                                             2 mg                                                     Compression weight   200 mg                                          ______________________________________                                    

The active ingredient, lactose and pregelatinised starch are blendedtogether and granulated with water. The wet mass is dried and milled.The magnesium stearate and Crospovidone are screened through a 250micron sieve and blended with the granule. The resultant blend iscompressed using suitable tablet punches.

Capsules

    ______________________________________                                        a.       Active ingredient    50 mg                                                    Pregelatinised Starch Ph.Eur.                                                                      148 mg                                                   Magnesium stearate USP                                                                             2 mg                                                     Fill weight          200 mg                                          ______________________________________                                    

The active ingredient and pregelatinised starch are screened through a500 micron mesh sieve, blended together and lubricated with magnesiumstearate (meshed through a 250 micron sieve). The blend is filled intohard gelatin capsules of a suitable size.

    ______________________________________                                        b.        Active ingredient   50 mg                                                     Lactose monohydrate USP                                                                           223 mg                                                    Povidone USP        12 mg                                                     Crospovidone NF     12 mg                                                     Magnesium stearate  3 mg                                                      Fill weight         300 mg                                          ______________________________________                                    

The active ingredient and lactose are blended together and granulatedwith a solution of Povidone. The wet mass is dried and milled, Themagnesium stearate and Crospovidone are screened through a 250 micronsieve and blended with the granule. The resultant blend is filled intohard gelatin capsules of a suitable size.

CCK-B, Receptor Binding Affinity

CCK-B receptor binding studies were carried out using HeLa cellmembranes which had been stabily transfected with the human CCK-Breceptor cloned from temporal cortex cDNA library.

Measurement of CCK-B binding affinity.

The transfected HeLa cell membranes were incubated with 30 pM [¹²⁵]BH-sCCK-8 in the presence of various concentrations of the testcompound (1 pM to 1 μM). All experiments were performed in an assayvolume of 250 μl. Membranes were harvested onto GF/C glass fibre filterpaper (Whatman, UK) by rapid filtration using a Cell Harvester (Brandelmodel M-24R) and washed three times with HEPES Wash buffer chilled to 4°C. The radioactivity trapped on individual filter discs was counted over60 seconds using a gamma counter (Mini Gamma counter, LKB, Wallac,Finland) at a counting efficiency of 77%. A control experiment was alsocarded out in the absence of a test compound.

Analysis of the data was performed by computer-assisted non-linearregression (ALLFIT programmes DeLean et al., 1978;). IC₅₀ values for thetest compounds were convened to K_(i) values using the Cheng & Prussofequation (K_(i) =IC₅₀ /(1+[L]/K_(D))) (Cheng and Prussof, 1973). Resultsobtrained with representative compounds of the invention in this testare given below and expressed as pKi values.

CCK-A Receptor Binding Affinity

CCK-A receptor binding studies were carried out using COS-M6 cellmembranes which have been transiently transfected with human gallbladder CCK-A receptor cDNA.

The clone was transiently transfected into COS-M6 cells grown to 80%confluency using the dimethylaminoethyl - dextran method based on themethod of Seed and Araffo. Proc. Natl, Acad, Sci. USA 84, 3365 1987. Therequired transfected cell membranes were then isolated in a conventionalmanner.

The affinity of compounds of the invention for the CCK-A receptor wasdetermined using the procedures described above for the CCK-B receptorhowever, in these experiments the test compound was tested atconcentrations in the range 10 pM to 10 μM.

CCK-B Binding Studies

    ______________________________________                                        Example No      pKi                                                           ______________________________________                                        1                   8.5                                                       1         (isomer 1)                                                                              8.5                                                       1         (isomer 2)                                                                              8.1                                                       2                   8.7                                                       3                   8.4                                                       4                   8.8                                                       7                   8.3                                                       8                   8.6                                                       10                  8.4                                                       12                  9.0                                                       14                  8.5                                                       15                  8.8                                                       20                  8.7                                                       ______________________________________                                    

The compounds of the invention are essential non-toxic atheraapeutically active doses. Thus no untoward effects were observedwhen the compound of Example 1 (isomer 1) was administered to thegastrin fistula rat of doses of 0.3 and 1 mg/kg iv at these dosesgastric acid secretion was significally inhibited.

We claim:
 1. Compounds of the formula (I) ##STR21## and physiologicallyacceptable salts thereof wherein the group NR₁ R₂ represents a 5-7membered saturated heterocylic ring which may be substituted by one ortwo methyl groups;R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or phenyl optionallysubstituted by 1 or 2 halogen atoms; R₄ is phenyl or phenyl substitutedby one or two groups selected from halogen, C₁₋₄ alkyl, trifluoromethyl,trifluoromethoxy or (CH₂)_(n) R₅ wherein n is zero or 1 and R₅represents C₁₋₄ alkoxy, hydroxy, nitro, cyano, CO₂ R₆, S(O)_(p) CH₃, NR₇R₈, CONR₇ R₈, SO₂ NR₇ CO(C₁₋₄ alkyl), tetrazolyl, carboxamidotetrazolyl,or a 3-trifluoromethyl 1,2,4-triazolyl; R₆ is hydrogen, C₁₋₄ alkyl orbenzyl; R₇ is hydrogen or C₁₋₄ alkyl, R₈ is hydrogen, C₁₋₄ alkyl, SO₂CH₃ or SO₂ CF₃, X represents hydrogen, C₁₋₄ alkyl or halogen; m is zero,1 or 2, and p is zero, 1 or
 2. 2. Compounds as claimed in claim 1wherein NR₁ R₂ represents pyrrolidino, 2,5-dimethylpyrrolidino,piperidino, 3,3-dimethylpiperidino, 4,4-dimethylpiperidino or2,6-dimethylpiperidino.
 3. Compounds as claimed in claim 1 wherein NR₁R₂ represents pyrrolidino.
 4. Compounds as claimed in claim 1 wherein R₃represents phenyl, 2-fluorophenyl or cyclohexyl.
 5. Compounds as claimedin claim 1 wherein R₃ represents cyclohexyl.
 6. Compounds as claimed inclaim 1 wherein R₄ represents phenyl, 3-methylphenyl,3,5-dimethylphenyl, 3-dimethylaminophenyl, 4-fluorophenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl,3-carboxamidophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or3-(1H)-tetrazol-5-yl-phenyl.
 7. Compounds as claimed in claim 1 whereinR₄ represent phenyl, 4-fluorophenyl, 3-dimethylaminophenyl,3-carboxylphenyl, 3-carboxymethylphenyl or 3-(1H)-tetrazol-5-yl-phenyl.8.1-[1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-3-(4-fluoro-phenyl)ureaand enantiomers thereof.
 9. A compound selectedfrom3-{3-[1-Cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid;(3-{3-[1-(2-Fluoro-phenyl)-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-phenyl)-aceticacid;3-{3-[1-[2-(3,3-Dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-(2-fluoro-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-ureido}-benzoicacid, and enantiomers thereof.
 10. Compounds as defined in claim 1 foruse in therapy.
 11. A pharmaceutical composition comprising a compoundas defined in claim 1 in admixture with one or more physiologicallyacceptable carriers or excipients.
 12. A method of treatment of a mammalincluding man for conditions where modifications of the effects ofgastrin and/or CCK is of therapeutic benefit comprising administrationof an effective amount of a compound as defined in claim
 1. 13. Apharmaceutical composition comprising a compound as claimed in claim 8in admixture with one or more physiologically acceptable carriers orexcipients.
 14. A method of treatment of a mammal including man forconditions where modifications of the effects of gastrin and/or CCK isof therapeutic benefit comprising administration of an effective amountof a compound as claimed in claim
 8. 15. Compounds as claimed in claim 1wherein:NR₁ R₂ represents pyrrolidino, 2,5-dimethylpyrrolidino,piperidino, 3,3-dimethylpiperidino, 4,4-dimethylpiperidino or2,6-dimethylpiperidino; R₃ represents phenyl, 2-fluorophenyl orcyclohexyl; and R₄ represents phenyl, 3-methylphenyl,3,5-dimethylphenyl, 3-dimethylaminophenyl, 4-fluorophenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl,3-carboxamidophenyl, 3-carboxylphenyl, 3-carboxymethylphenyl or3-(1H)-tetrazol-5-yl-phenyl.
 16. Compounds as claimed in claim 1wherein:NR₁ R₂ represents pyrrolidino, piperidino, or3,3-dimethylpiperidino; R₃ represents 2-fluorophenyl or cyclohexyl; Xrepresents hydrogen; and R₄ represents phenyl, 4-fluorophenyl,3-dimethylaminophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or3-(1H)-tetrazol-5-yl-phenyl.